LIVER-INJURY AND EXPRESSION OF CYTOCHROMES P450 - EVIDENCE THAT REGULATION OF CYP2A5 IS DIFFERENT FROM THAT OF OTHER MAJOR XENOBIOTIC-METABOLIZING CYP ENZYMES

The purpose of this study was to find out how liver injury caused by t wo well-known hepatotoxins, chloroform and thioacetamide, alters the e xpression of hepatic xenobiotic metabolizing cytochrome P450 (CYP) enz ymes of DBA/2N mice. Dose-dependent toxic effects of the two hepatotox ins were verified by histological examination. Along with the toxicity , intense staining of immunoreactive material was detected in the cent rilobular zone, with anti-CYP2A5 antibody in hepatic tissue. This appa rent increase in the expression of Cyp2a-5 was verified by Northern bl ot and Western blot analyses and by determining the enzymatic activity , coumarin 7-hydroxylase, in hepatic tissue. The results suggest that liver injury due to these hepatotoxins increases the expression of Cyp 2a-5 and that the expression is pretranslationally regulated. The incr eased expression of Cyp2a-5 is in contrast with that of other xenobiot ic metabolizing CYPs because a dose-dependent decrease of the total he patic P450 content and either a decrease or no change in the levels of CYP1A, 2B, 2C, 2E1, and 3A4 were observed. The results suggest that e ssential differences exist in the regulation of CYP2A5 and other major xenobiotic metabolizing CYP enzymes and that in a damaged liver CYP2A 5 may be a major catalyst of xenobiotic metabolism. (C) 1996 Academic Press Inc.